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Interleukin-6 Receptor Blockade can Increase the Risk of Nonalcoholic Fatty Liver Disease: Indications From Mendelian Randomization

Background: Interleukin-6 receptor (IL-6R) blockade has been approved for inflammation-associated diseases and whether it is effective in treating non-alcoholic fatty liver disease (NAFLD) is still unknown. Methods: A target-based Mendelian randomization was performed to appraise whether inhibiting...

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Autores principales: Li, Shuxuan, Chen, Lanlan, Lv, Guoyue
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9209733/
https://www.ncbi.nlm.nih.gov/pubmed/35747747
http://dx.doi.org/10.3389/fphar.2022.905936
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author Li, Shuxuan
Chen, Lanlan
Lv, Guoyue
author_facet Li, Shuxuan
Chen, Lanlan
Lv, Guoyue
author_sort Li, Shuxuan
collection PubMed
description Background: Interleukin-6 receptor (IL-6R) blockade has been approved for inflammation-associated diseases and whether it is effective in treating non-alcoholic fatty liver disease (NAFLD) is still unknown. Methods: A target-based Mendelian randomization was performed to appraise whether inhibiting the IL-6 signaling pathway via IL-6R blockade can reduce the risk of NAFLD. The previously established genetic proxy SNP rs2228145 was mainly used to appraise the therapeutic effects and the genetic-predicted circulating IL-6 level was treated as the exposure with ∼30,000 samples. The genetic association between SNP rs2228145 (A > C) and NAFLD was obtained from non-FinnGen GWAS (1,483 cases and 17,781controls) and FinnGen GWAS (894 cases and 217,898 controls). The causal effects were estimated using a Wald ratio method and were combined using a fixed-effects meta-analysis. Furthermore, the SNP rs12048091 was employed as another proxy in the sensitivity analysis. Results: The positive control analysis suggested the SNP rs2228145 can mimic the effects of IL-6R blockade where inhibiting IL-6 signaling can reduce the risk of rheumatoid arthritis [OR = 0.68 (0.58, 0.80)] and coronary heart disease [OR = 0.75 (0.68, 0.84)]. This Mendelian randomization analysis suggested that IL-6R blockade can adversely increase the risk of NAFLD in the non-FinnGen GWAS [OR = 1.99 (1.27, 3.13)] while not significant in the FinnGen consortium. The fixed-effects meta-analysis indicated inhibiting the IL-6 signaling pathway can reduce the risk of NAFLD [OR = 1.80 (1.26, 2.57)]. When including SNP rs12048091 as the genetic instrument, the meta-analysis using two genetic variants also indicated a similar effect on NAFLD [OR = 1.83 (1.32, 2.53)]. There was no heterogeneity in the whole analysis. Conclusion: Our Mendelian randomization suggested inhibiting the IL-6 signaling pathway via IL-6R blockade might increase the risk of NAFLD, suggesting IL-6R should play a protective role in NAFLD.
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spelling pubmed-92097332022-06-22 Interleukin-6 Receptor Blockade can Increase the Risk of Nonalcoholic Fatty Liver Disease: Indications From Mendelian Randomization Li, Shuxuan Chen, Lanlan Lv, Guoyue Front Pharmacol Pharmacology Background: Interleukin-6 receptor (IL-6R) blockade has been approved for inflammation-associated diseases and whether it is effective in treating non-alcoholic fatty liver disease (NAFLD) is still unknown. Methods: A target-based Mendelian randomization was performed to appraise whether inhibiting the IL-6 signaling pathway via IL-6R blockade can reduce the risk of NAFLD. The previously established genetic proxy SNP rs2228145 was mainly used to appraise the therapeutic effects and the genetic-predicted circulating IL-6 level was treated as the exposure with ∼30,000 samples. The genetic association between SNP rs2228145 (A > C) and NAFLD was obtained from non-FinnGen GWAS (1,483 cases and 17,781controls) and FinnGen GWAS (894 cases and 217,898 controls). The causal effects were estimated using a Wald ratio method and were combined using a fixed-effects meta-analysis. Furthermore, the SNP rs12048091 was employed as another proxy in the sensitivity analysis. Results: The positive control analysis suggested the SNP rs2228145 can mimic the effects of IL-6R blockade where inhibiting IL-6 signaling can reduce the risk of rheumatoid arthritis [OR = 0.68 (0.58, 0.80)] and coronary heart disease [OR = 0.75 (0.68, 0.84)]. This Mendelian randomization analysis suggested that IL-6R blockade can adversely increase the risk of NAFLD in the non-FinnGen GWAS [OR = 1.99 (1.27, 3.13)] while not significant in the FinnGen consortium. The fixed-effects meta-analysis indicated inhibiting the IL-6 signaling pathway can reduce the risk of NAFLD [OR = 1.80 (1.26, 2.57)]. When including SNP rs12048091 as the genetic instrument, the meta-analysis using two genetic variants also indicated a similar effect on NAFLD [OR = 1.83 (1.32, 2.53)]. There was no heterogeneity in the whole analysis. Conclusion: Our Mendelian randomization suggested inhibiting the IL-6 signaling pathway via IL-6R blockade might increase the risk of NAFLD, suggesting IL-6R should play a protective role in NAFLD. Frontiers Media S.A. 2022-06-07 /pmc/articles/PMC9209733/ /pubmed/35747747 http://dx.doi.org/10.3389/fphar.2022.905936 Text en Copyright © 2022 Li, Chen and Lv. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Li, Shuxuan
Chen, Lanlan
Lv, Guoyue
Interleukin-6 Receptor Blockade can Increase the Risk of Nonalcoholic Fatty Liver Disease: Indications From Mendelian Randomization
title Interleukin-6 Receptor Blockade can Increase the Risk of Nonalcoholic Fatty Liver Disease: Indications From Mendelian Randomization
title_full Interleukin-6 Receptor Blockade can Increase the Risk of Nonalcoholic Fatty Liver Disease: Indications From Mendelian Randomization
title_fullStr Interleukin-6 Receptor Blockade can Increase the Risk of Nonalcoholic Fatty Liver Disease: Indications From Mendelian Randomization
title_full_unstemmed Interleukin-6 Receptor Blockade can Increase the Risk of Nonalcoholic Fatty Liver Disease: Indications From Mendelian Randomization
title_short Interleukin-6 Receptor Blockade can Increase the Risk of Nonalcoholic Fatty Liver Disease: Indications From Mendelian Randomization
title_sort interleukin-6 receptor blockade can increase the risk of nonalcoholic fatty liver disease: indications from mendelian randomization
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9209733/
https://www.ncbi.nlm.nih.gov/pubmed/35747747
http://dx.doi.org/10.3389/fphar.2022.905936
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